The close integration of immune and metabolic responses associated with obesity lead to the development of metabolic diseases such as insulin resistance, diabetes, and atherosclerosis. However, the endogenous molecules that signal metabolic stress and the mechanisms that sense and relay such signals to metabolic and immune response systems are incompletely understood. The double stranded RNA-activated protein kinase PKR is activated in response to pathogens and nutrients, and work by our laboratory and others suggests that PKR plays an important role in integrating signaling networks that modulate inflammation and the development of insulin resistance. Based on our preliminary data we propose that the study of PKR activation represents an opportunity to identify the metabolic signals and novel mechanisms at play in immunometabolic regulation. Therefore, the objective of this proposal is to characterize the endogenous lipids and RNAs that modulate PKR activity and the formation of the active PRK complex in the setting of metabolic stress, with the goal of translating these findings to a broader understanding of the molecular signals that contribute to the integration of metabolic stresses and inflammation in obesity. We believe that successful completion of this work has the potential to highlight new therapeutic targets and strategies for use in the fight against the epidemic of obesity and related pathologies.